ABSTRACT. Chronic fatigue syndrome (CFS) is an illness associated
with severe activity limitation and a characteristic pattern of symptoms
despite a relatively normal physical examination and routine laboratory
evaluation. The recent description of delayed orthostatic hypotension in
patients with CFS, and previous findings of reduced red blood cell (RBC)
mass in other patients with orthostatic hypotension not known to have CFS,
led us to measure RBC mass and plasma volume in 19 individuals (15 female,
four male) with well characterized, severe CFS. RBC mass was found to be
significantly reduced (p < 0.001) below the published normal range in
the 16 women, being subnormal in 15 (93.8%) of them as well as in two of
the four men. Plasma volume was subnormal in 10 (52.6%) patients and total
blood volume was below normal in 12 (63.2%). The high prevalence and frequent
severity of the low RBC mass suggest that this abnormality might contribute
to the symptoms of CFS by reducing the oxygen-carrying power of the blood
reaching the brain in many of these patients.

Chronic fatigue syndrome (CFS) is an illness
of unknown etiology, characterized by profound exhaustion, orthostatic
intolerance, and numerous somatic complaints. The illness is characterized
by a severe activity restriction despite normal or relatively minor abnormalities
on physical examination and routine laboratory studies. CFS occurs in both
children and adults (1-5), may be sudden or gradual in onset (6,7), and
follows a variety of initiating insults (2,8,9).

Recent observations have linked CFS with neurally
mediated hypotension (10,11) and delayed orthostatic intolerance (12).
Previous studies of the pathogenesis of both hyperadrenergic and hypoadrenergic
orthostatic hypotension have shown that, in addition to the almost invariable
finding of excessive orthostatic blood pooling in the lower limbs (13,14)
attributable to subnormal venous constriction of the legs (15), reduction
of red blood cell (RBC) mass is frequently present (13,16). For this reason
we have explored the prevalence of abnormalities in the total circulating
volumes of RBC's, plasma, and whole blood in a series of nineteen patients
with well documented CFS.

METHODS

The 19 patients included in this paper are
drawn from the clinical practice of one of the investigators (DSB) and
most had been followed clinically for many years. Nine patients underwent
autonomic nervous system testing in Syracuse, the results of which will
be reported separately. Subjects were selected sequentially if they met
the 1994 Center for Disease Control (CDC) diagnostic criteria for CFS (17),
met the severity criteria of less than five hours of upright activity daily,
and wished to participate in the study.

Severity instruments used at the time of the
blood volume studies included (1) sum of the visual analog scores for 12
prominent symptoms seen in CFS (7); (2) a modified Karnofsky score (7);
(3) estimation of total activity (7); and (4) the Fisk Fatigue Impact Scale
score (18). These four rating scales had been taken on numerous occasions
on the majority of the patients reported in the present paper and have
been remarkably consistent over a period of years despite a variety of
therapeutic trials in which the patients participated (data not shown).
While many of the patients in this study have experienced episodes of depression
in the past, none was considered to have emotional factors as the cause
of his or her illness. None of the patients in this study were taking mineralocorticoids,
diuretics, or other medications known to influence circulating blood volume
at the time of the study. One patient had type II diabetes mellitus with
blood sugar in the normal range with oral hypoglycemic medication. The
demographics and severity ratings of the patient population are presented
in Table 1.

RBC mass and plasma volume were determined
with standard methods, using 51Cr-labeled autologous red blood cells (19)
and 125I-labeled human serum albumin (19), respectively, in five university
affiliated radiology departments. Normative data was taken from published
studies (20), and no healthy controls were evaluated at the time of this
study.

Blood pressure measurements (Table 2) were
the average of pressures taken during office visits, in the course of routine
follow up of their illness. The peripheral hematocrit (Table 2) was the
average of peripheral hematocrits recorded in the patients' chart during
their illness. There was no unusual variation between the average hematocrit
and the hematocrit taken nearest to the blood volume studies (data not
shown). Whole body hematocrit was calculated from the circulating blood
volume data (RBC mass/total blood volume).

Table 1 shows that the patients included 15 women and 4 men, aged 14-50
years, whose ability to perform normal upright activity had been reduced
to between one and four hours per day, estimated at 20% to 30% of their
previous capacity. The sum of visual analog scores and Fisk Fatigue Impact
Scale scores indicate the degree of their incapacitation.

RBC Mass, Plasmu Volume,and Whole Blood Volume Measurements

The data in Table 2 show that RBC mass was
below the normal range (25-30 mL/Kg) in 14 of 15 female patients and 2
of 4 males. In the 15 female patients, the RBC mass (Mean 18.8, SD 3.1
mL/Kg) was significantly lower than the 20 normal female subjects reported
by Huff and Feller (20), viz. 24.4 + 2.6 mL/Kg (p < 0.001), as displayed
in Table 3. The small number (4) of male patients precluded determination
of statistical significance of the differences between their data and those
of normal subjects reported by Huff and Feller.

Plasma volume was quite variable in our patients,
being below the normal range in 10, normal in 4 and elevated in 2 of the
15 female subjects (Table 2). The mean plasma volume in these 15 individuals
(38.77 +/-19.5 mL/Kg) was not significantly different from the mean of
normal female subjects, 34.8 + 3.2 mL/Kg (18). Similarly, the total blood
volume in our 15 female subjects (Mean 57.49, SD 20.47) was not significantly
different from the values found in the same 20 normal females (58.9+/-4.9
mL/Kg).

It is evident from Table 2 that the peripheral
hematocrit was below 37% in only 4 of our
patients. In fact, mean peripheral hematocrit was significantly higher
(p > 0.01) than whole body hematocrit (i.e., RBC mass/total blood volume)
in our patient group. Blood pressures, measured in the sitting position,
were normal) (95-140/60-90) in all but one subject whose blood pressure
was 150/87.

The characteristic elements which comprise the chronic
fatigue syndrome (CFS) are asthenia, fatigue, orthostatic intolerance,
and numerous somatic complaints. The lack of detectable tissue damage in
routine laboratory testing has led to assumptions that CFS may be either
a trivial illness, a psychosomatic disorder, or a variant of depression.
Blood volume measurements have traditionally been used in the management
of polycythemia but not in the evaluation of CFS until recently (12).

TABLE 3Mean (+ S.D.) Blood Volume Results
in Female Patients

RBC mass (mL/Kg)Plasma volume (mL/Kg)Total blood volume (mL/Kg)

RBC mass = Red blood cell mass

Patients
n=15

24.4 +/-3.1
38.8 +/- 19.5
57.5 +/- 20/5

Normal Controls
n=20

24.4 +/- 2.6
34.8 +/- 3.2
59.2 +/- 4.9

p Value

<0.001
N.S
N.S.

Of the 19 patients reported here, abnormalities
in blood volume were very common. The most common, found in 16 of 19 patients,
was a reduction in red blood cell mass. Eleven subjects had low plasma
volumes, and total circulating blood volume was subnormal in 12 of 19 subjects.
In some individuals this abnormality was strikingly severe. Patient #15,
for example, had an RBC mass of 12.9 mL/Kg, which is 46% of the expected
normal, and a total blood volume of 35.8 mL/Kg, which represents 49.7%
of the expected normal value (21). Her peripheral hematocrit was not impressively
low at 33.8%, presumably because of the symmetrical reduction in both RBC
mass and plasma volume. In other patients the plasma volume was normal
or even elevated in the face of a low RBC mass, and in nqne of these patients
was the RBC mass abnormality detected by conventional interpretation of
the peripheral hematocrit.

All of the subjects in this study had symptoms
of orthostatic intolerance which probably contributed to their activity
restriction, but tilt table and autonomic nervous system testing was not
carried out systematically in these individuals. Normal sitting blood pressures
were recorded in all patients under office visit circumstances, except
for relatively low values in three and a mildly elevated blood pressure
in one. Some of these patients have been tested subsequently and found
to have delayed orthostatic hypotension (12), which may be characteristic
for CFS (11,12). In general, blood pressure measurements were not predictive
of the results of circulating blood volume measurements.

A subnormal RBC mass and/or decreased
circulating blood volume may well result in diminished cerebral blood flow
with subnormal oxygen-carrying capacity (22). These abnormalities, by reducing
cerebral oxygenation, might well be important factors in the pathogenesis
of chronic fatigue and deserve further evaluation. It is important to note,
however, that 3 of the 19 patients in this study had normal RBC mass and
plasma volume, and thus a deficiency of circulating blood volume could
not account for their symptomatology. Clinically, there was no obvious
difference in the degree of fatigue, orthostatic intolerance, or somatic
symptoms in these patients as compared with those who'se RBC mass was reduced
(Table 1).

The high prevalence of reduced RBC mass in
our patients with severe CFS suggests that this abnormality may well be
important to the pathogenesis of their persisting symptoms, though not
necessarily in that of the initiating event. While most frequently seen
after a viral infection and with no obvious precipitating cause (1), CFS
has also developed after ciguatera poisoning (23), head injury (personal
observation), and lead poisoning (personal observation). Post-polio fatigue
bears striking resemblance to CFS (24,25). Hereditary factors may also
play a role, perhaps through effects on autonomic nervous system function.
Thus, whatever its initiating cause, CFS may be perpetuated, at least in
part, by low RBC mass in many patients.

In this study, matched control subjects were
not assessed for circulating blood volume, and thus the data presented
here should be considered a preliminary report. Since significant reduction
of RBC and whole blood volume may be among the few objectively demonstrable
laboratory abnormalities in the majority of patients during the chronic
stages of CFS, we believe that further studies of these changes would be
worthwhile.